Despite the availability of antibiotics, tuberculosis remains a major problem worldwide, killing 1.7 million people in 2006. Rational design of an efficacious new vaccine for tuberculosis demands a more complete understanding of the host response to Mycobacterium tuberculosis. The adaptive immune response to M. tuberculosis is crucial for control of bacterial growth, but it cannot eliminate infection. Initiation, expansion, and effector mechanisms of adaptive immunity to this pathogen each rely on the presentation of bacterial peptides to antigen specific T cells, whether to naive T cells in the lung-draining lymph node or to mature Th1 effector cells in the lungs of infected individuals. Therefore, the availability of bacterial antigens and the functional properties of host antigen presenting cells at both of these sites critically determine the success of the adaptive immune response to M. tuberculosis. This proposal has two general goals: 1) To define the cellular events that initiate adaptive immunity to M. tuberculosis, I will characterize the kinetics of M. tuberculosis derived antigen presentation during mouse infection. I will also determine the contribution of individual APC subsets and the relative contribution of M. tuberculosis-infected versus uninfected cells to initiation of adaptive immunity. 2) To identify and quantitate mechanisms that limit the efficacy of the adaptive immune response to M. tuberculosis, I will determine the antigen presentation capability of antigen presenting cells in the lungs of infected mice throughout the course of infection. Furthermore, I will quantitate the contribution of downregulation of Ag85B gene expression by M. tuberculosis during the chronic phase of infection to the inability of adaptive immunity to eradicate M. tuberculosis. These studies will provide an improved understanding of the adaptive immune response to M. tuberculosis, aiding future vaccine development efforts by identifying the critical cell populations and events that initiate adaptive immunity. Elucidation of the shortcomings of endogenous immunity to this successful human pathogen also promises to offer direction to development of therapeutic vaccines and contribute much to the knowledge of the general immunology of'the respiratory tract.